Targeting ceramide synthesis in Parkinson’s disease

Current Parkinson’s disease therapies focus on restoring dopamine — treating symptoms without addressing what drives the disease. CeraLink is taking a fundamentally different approach by targeting the ceramide synthesis and membrane dysfunction that underlies neurodegeneration.

Parkinson’s disease is growing in prevalence with limited treatment options

Parkinson’s disease is a progressive neurodegenerative disorder characterized by the loss of dopamine-producing neurons in the brain. It leads to debilitating motor symptoms, cognitive impairment, psychiatric symptoms, and sleep disturbances.

Available treatments are aimed at restoring and maintaining dopamine levels, but they carry significant limitations:

They do not address non-motor symptoms and can exacerbate psychiatric side effects
They cause fluctuations in treatment effect and involuntary movements (dyskinesias)
Drug effect typically plateaus and declines after five to seven years of treatment
No available therapy can halt or slow the progression of the disease

There is a critical need for therapies that can address both symptoms and disease progression.

SPT overactivity drives neurotoxic deoxyceramide production

Serine palmitoyl transferase (SPT) is the rate-limiting enzyme in the production of ceramides and deoxyceramides. When SPT is overactive, it produces elevated levels of neurotoxic deoxyceramides that are incorporated into cell and organelle membranes. This leads to membrane dysfunction and affects critical cellular processes including mitochondrial function, lysosomal activity, autophagy, and synuclein aggregation/clearance.

Convergent evidence supports SPT inhibition as a therapeutic strategy

Genetic link

A genetic variant ties SPT activity to PD risk

A common single-nucleotide polymorphism rs1450522 is known to increase expression of active SPT and is associated with elevated Parkinson’s disease risk. Individuals carrying two copies of this variant produce significantly more ceramides and are at meaningfully higher risk of developing PD. This variant is also correlated with elevated plasma ceramide levels, supporting the potential for ceramides and deoxyceramides as peripheral biomarkers.

Pathological link

Deoxyceramides disrupt neuronal membranes in PD

Deoxyceramides — products of overactive SPT — are found in the brains of Parkinson’s disease patients. These neurotoxic lipids disrupt membrane properties, causing dysfunction in mitochondria and other membranous organelles. Membrane disruption in PD has been extensively documented and is thought to play a significant role in disease onset and progression.

Clinical link

An SPT inhibitor improved symptoms in PD patients

D-Serine, a naturally occurring amino acid that inhibits SPT, has been evaluated in a pilot clinical study in Parkinson’s disease patients. In a double-blind, placebo-controlled crossover trial, D-Serine treatment led to meaningful improvements in motor and behavioral symptoms as measured by the UPDRS rating scale. These results provide important clinical validation for the SPT inhibition mechanism.

See how CLNK-1 builds on this evidence Publications

Interested in learning more about CeraLink?

We welcome conversations with potential partners, investors, and collaborators who share our commitment to advancing new treatments for neurodegenerative disease.

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